1. Field of the Invention
The use of calcium phosphate and optionally a calcium aluminate (all associated phases, derivatives, and/or analogs thereof) as raw materials for the manufacture of artificial bone, artificial joints, in-vitro support structures, and support structure for tissue, cells, and/or organ growth and/or regeneration is provided. The use of slipcasting, slurrycasting or vibration casting in molds to generate the desired shapes of the artificial bones, joints and support structures of the invention, as well as generating the desired shapes by hand without a mold, are also provided. The present invention provides a functionalized composition comprising at least one calcium phosphate containing phase that is functionalized either on the surface of the calcium phosphate containing phase or within a porous scaffold of the calcium phosphate containing phase with a linker group comprising at least one of an organic acid molecule, a phosphonic acid, an amine, N,N-dicyclohexylcarbodiimide, and 3-maleimidopropionic acid N-hydroxysuccinimide ester, and combinations thereof, and one or more of another chemical moiety and/or one or more of a biologically active moiety, wherein the linker group provides for a reactive location for the attachment of either of the another chemical moiety or the biologically active moiety, or both, to the calcium phosphate containing phase, and optionally including wherein at least one of the calcium phosphate containing phases is in a monolithic form. Further, a functionalized composition is provided having the calcium phosphate containing phase as described above and optionally a calcium aluminate containing phase that optionally is functionalized with one or a plurality of the above-mentioned linker groups for providing a reactive location for the attachment of other chemical and/or biologically active moieties to the calcium aluminate containing phase.
2. Description of the Background Art
Current artificial joints and bones are manufactured from apatites or metal, typically titanium. They are machined to the desired shape which is a costly and production inefficient method of construction. These materials, in order to be accommodated by the host, must exhibit porosity so as to accommodate cell growth within the three dimensional structure. In particular, porosity is important where the part comes in contact with the host's natural structure (bone). This is due to the need for the host's bone to grow into and vascularize the artificial structure in order to develop the necessary bond between the two and reduce bone degeneration at the interface. Although attempts have been made in the current materials known by those skilled in the art to introduce porosity, the resulting structure is less than ideal. In most cases, artificial joints and other structures need to be replaced over time because the surrounding tissue and structure has degenerated. Pins, screws, rods and other structures are required to stabilize, bond and support the interface.
There is an identifiable need to create structures designed to support tissue growth, such as in artificial organ growth. The use of plastics as a support structure for tissue growth is known by those skilled in the art and has been accomplished by the use of organic polymers. These plastics and polymers are expensive when employed as artificial prostheses and lack porosity.
Bone is a very complex organ made of cells and extracellular matrix. It is constantly being rebuilt through the interactions of osteoblasts and osteoclasts. Bone functions include maintaining blood calcium levels, providing mechanical support to soft tissues, and serving as levers for muscle action, supporting haematopoiesis, and housing the brain and spinal cord.
The treatment of bone diseases and fractures represents one of the largest markets for regenerative medicine, estimated to reach $1.8 billion by 2008. Annually, there are over 500,000 bone graft procedures in the United States. Of these procedures, only 10% involve synthetic sources.
Bone fracture and damage result in more than 1.3 million surgical procedures each year only in the United States. Autografts and allografts are considered the standard for treating these types of wounds. However, both methods have disadvantages. The failure rate of an autograft is controlled by the need of a second site of surgery. The necessity of a second site of surgery for donor material contributes to the failure rate of autograft procedures. Failure can be attributed to limited supply, inadequate size and shape, and the morbidity associated with the donor site; all of which are issues of concern. Allografts share some of these disadvantages, and in addition; the procedure raises questions associated with donor and recipient compatibility. The disadvantages of autografts and allografts have influenced the importance of synthetic bone implants. The calcium aluminate materials of the present invention are effective bone replacement material. It will be appreciated by those skilled in the art that the calcium aluminate materials of the present invention have a controlled porosity, high strength and ease of casting, and overcome many of the difficulties associated with currently available technology.
Current implant technologies involve the use of titanium and other metals which is costly due to the need to machine the material to the desired shape. These materials, in order to be accommodated by the host, must exhibit porosity where the implant comes in contact with the host's bone. This is due to the need for the host's bone to grow into and vascularize the artificial structure in order to develop the necessary bone between the two, and reduce bone degeneration at the interface. In addition, there is bone loss due to the hardness differential between the implanted metal and natural bone. Plastics are often inserted between the two to stop this from occurring but this affects the ability of the appropriate interface to form. Metal implants require the use of rods, pins, and screws to be held into place and often need to be replaced over time.
As stated herein, methods to heal damaged bone include autografts, allografts, and the use of synthetic sources. Autografts are the standard for repairing skeletal defects, however, there are disadvantages associated with this type of treatment. Reasons for failed autografts include the need for a second site of surgery, limited supply, inadequate graft size and shape, and morbidity associated with the donor site. Allografts present similar disadvantages and are further complicated by issues related to the potential of pathogenic transmission.
Synthetic sources and bone substitutes are being evaluated to overcome the difficulties involved with autografts and allografts. To be effective in healing bone defects a material needs to have certain qualities. A scaffold should be porous to allow nutrients to permeate, and permit vascularization. It should be osteoconductive to enable new bone tissue formation, and it should degrade to allow resorbtion. Demineralized bone matrix, hydroxyapatite and tricalcium phosphate granules and scaffolds, organic sponges, synthetic sponges, porous ceramics, and collagen discs have all been used as bone substitutes or vehicles to deliver bone cells or growth factors.
Current artificial joints and bones are manufactured from apatites or metal, typically titanium. They are machined to the desired shape which is a costly and production inefficient method of construction. These types of materials are not all optimized for porosity, which is crucial for a successful implant material. There is a need for the host's bone to grow into and vascularize the artificial structure in order to develop the necessary bond between the artificial and natural bone matrix. This will result in reduced bone degeneration at the interface of the implant material and natural bone.
Research to date has mainly focused on calcium aluminates for use in the dental industry as a direct restorative dental material wherein the calcium aluminate cement is used as a fine bonding agent in the matrix and is not the primary support aggregate.
Calcium aluminates do not cause an inflammatory response when placed into in-vivo scenarios. Klawitter and Hulbert studied the influence of pore structures on calcium aluminate pellets. Calcium aluminates were implanted into the midshaft region of dog femurs and showed no inflammatory response. The Klawitter and Hulbert study showed that tissue around the porous implants healed more quickly.
Other studies have shown that calcium aluminates are able to support the proliferation of cells. Kalita studied the porosity of calcium aluminates and determined that some of the pores of the calcium aluminates were almost filled with a monolayer of cells. Kalita used fused deposition process to build materials using a computer program which constructs the material layer by layer.
In spite of this background art, there remains a very real and substantial need for porous bodies comprising calcium phosphate and optionally calcium aluminate, its phases, derivatives and/or analogs thereof, wherein the porous bodies are capable of functioning as artificial bone, artificial joints, in-vitro support structures, and in-vivo support structures for cells, tissues, organs and nerve growth and regeneration.